Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo

Abstract

Nitric oxide may be a key mediator of excitotoxic neuronal injury in the central nervous system. We examined the effects of the neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) on excitotoxic striatal lesions. 7-NI significantly attenuated lesions produced by intrastriatal injections of NMDA, but not kainic acid or alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) 7-NI attenuated secondary striatal excitotoxic lesions produced by the succinate dehydrogenase inhibitor malonate, and the protection was reversed by L- arginine but not by D-arginine, 7-NI produced nearly complete protection against striatal lesions produced by systemic administration of 3-nitropropionic acid (3-NP), another succinate dehydrogenase inhibitor, 7-NI protected against malonate induced decreases in ATP, and increases in lactate, as assessed by 1H magnetic resonance spectroscopy. 7-NI had no effects on spontaneous electrophysiologic activity in the striatum in vivo, suggesting that its effects were not mediated by an interaction with excitatory amino acid receptors. 7-NI attenuated increases in hydroxyl radical, 8-hydroxy-2-deoxyguanosine and 3-nitrotyrosine generation in vivo, which may be a consequence of peroxynitrite formation. The present results implicate neuronal nitric oxide generation in the pathogenesis of both direct and secondary excitotoxic neuronal injury in vivo. As such they suggest that neuronal nitric oxide synthase inhibitors may be useful in the treatment of neurologic diseases in which excitotoxic mechanisms play a role.

Influence of the antioxidants vitamin E and idebenone on retinal cell injury mediated by chemical ischemia, hypoglycemia, or oxidative stress

“…Inducible NOS knockouts also reduced the susceptibility to ischemic brain injury [42]. Moreover, NOS inhibitors protected against excitotoxic neuronal injury [43]. Although we found previously that nitro G -w-arginine reduced the activity of NOS in retinal cells in culture [29], exposure to nitro G -w-arginine was not effective against retinal cell injury up to 12 h upon chemical ischemia, hypoglycemia or oxidative stress ( Table 1).…”

“…Although we found previously that nitro G -w-arginine reduced the activity of NOS in retinal cells in culture [29], exposure to nitro G -w-arginine was not effective against retinal cell injury up to 12 h upon chemical ischemia, hypoglycemia or oxidative stress ( Table 1). The failure of nitro G -warginine to increase the viability of retinal cells upon hypoglycemia or ischemia may also be related with a reduced involvement of the NMDA receptors in cell injury (Table 1), because the generation of nitric oxide has been implicated in the excitotoxic neuronal injury mediated by activation of the NMDA receptors [43,44]. Recently, we showed an inhibition of NOS activity after 15 min ascorbate/Fe 2ϩ -induced oxidative stress in retinal cells [29], explaining the inefficacy of the inhibitor of NOS after withdrawal of the oxidant inducers.…”

Mitochondrial Nitric Oxide Mediates Decreased Vulnerability of Hippocampal Neurons from Immature Animals to NMDA

“…In neurons from mature rats, NO does not mediate NMDAinduced ⌬⌿ m dissipation but does mediate NMDA toxicity In contrast to protecting neurons from NMDA toxicity, as seen in immature neurons, NMDA-induced NO production has been shown to kill neurons in the brains of mature animals, as well as in cultured embryonic neurons maintained in vitro for Ͼ10 d (Dawson et al, 1991;Schulz et al, 1995;Keelan et al, 1999). We wanted, therefore, to define how the role of NMDA-induced NO production changes during postnatal development.…”

Nitric oxide mediates neurodegeneration and breakdown of the blood-brain barrier in tPA-dependent excitotoxic injury in mice

“…Despite the increased presence of NO during excitotoxicity, its specific role remains unclear. Depending on the context in which NO is produced, it appears to elicit either a degenerative effect (Dawson et al, 1991;Gabriel et al, 2000;Schulz et al, 1995) or has negligible effects on excitotoxicity (Lerner-Natoli et al, 1992;Pauwels and Leysen, 1992). NO might even exhibit protective properties by reducing oxidative stress (Chiueh, 1999;Kiprianova et al, 1997).…”